The long-term goal of the research is to increase our understanding of how synaptic transmission is modulated and regulated. The proposed research will examine excitatory monosynaptic connections between the A and B neurons in the cerebral ganglion of Aplysia. Low frequency stimulation (<0.01 Hz) of the presynaptic A neurons induces a marked synaptic depression. The proposed research will elucidate the biochemical and biophysical mechanisms mediating depression. The experiments will use voltage clamp recording from the presynaptic A neurons to measure the changes in membrane currents during synaptic depression. This will test the hypothesis that depression is due to an increase in K+ current, a decrease in Ca2+ current, or both. Cyclic AMP and its activators decrease EPSP amplitudes. The proposal will test the hypothesis that depression is mediated by cyclic AMP. The membrane current changes induced by activating cyclic AMP will be compared to those caused by low frequency firing. Adenosine and adenosine agonists also decrease EPSP amplitudes. The proposal will also test the hypothesis that synaptic depression is mediated by adenosine. Adenosine should produce the same changes in membrane current as low frequency activity. Finally, the adenosine receptors on the A and B neurons will be characterized using specific adenosine A1 and A2 agonists and antagonists. These studies will generate insights into the cellular mechanisms underlying synaptic plasticity and activity-dependent regulation of synaptic transmission.